As a major mechanism in maintaining pressure homeostasis, the renin-angiotensin system has been shown to participate in the pathophysiology of a variety of hypertensive states. However, treatment of renin-initiated hypertension is often limited to the Beta-blocker of propranolol, possibly mediated by a neurogenic mechanism. In addition, diagnosis of angiotensin-related hypertensions by teprotide or captopril and by saralasin often gave different results, due to the nonspecific actions of these coverting enzyme inhibitors on other pressure-regulating systems as well as the ineffectiveness of saralasin as an angiotensin inhibitor. In an attempt to abolish the renin-angiotensin cascade in a site-specific manner, this application proposes multiple approaches to increase the selectivity of the renin inhibitors through preferential distribution to kidney as well as transition-state binding to the enzyme. In addition, methods for improving the affinity and proteolytic resistance of a potent angiotensin antagonist are described, with the resulting inhibitors having multiple applications in conformational analyses and mechanismic elucidation of the hormone-receptor interactions. The proposed experiments will use peptide synthesis to explore the possibility of developing i) pepstatin-containing substrate-inhibitors of renin, and ii) super-binding angiotensin inhibitors with minimal agonistic activities, effective in suppressing renin or angiotensin-induced hypertension in the rats. It is hoped that these inhibitors will contribute to the understanding and ultimate control of angiotensin-related hypertensions, and provide a diagnostic tool to differentiate possible renin-angiotensin abnormality of different orgins.